Abstract 16251: Ondansetron Inhibits Apamin-Sensitive Small Conductance Ca2+ Activated K+ Currents in Pacing Induced Failing Rabbit Hearts
Introduction: Ondansetron, a widely prescribed 5-HT3 receptor blocker, has been implicated in drug-induced LQTS (diLQT) including patients with heart failure. Because ondansetron at therapeutic concentrations do not block IKr or IKs, the mechanism of QTc prolongation with ondansetron remains unknown. Our previous studies showed that apamin-sensitive small conductance, Ca2+ activated K+ (SK) currents (IKAS) is important in ventricular repolarization in failing ventricles.
Hypothesis: We hypothesized that ondansetron at therapeutic concentrations causes action potential duration (APD) prolongation by IKAS inhibition in failing ventricles.
Methods: Optical mapping of the membrane potential was performed in 7 Langendorff-perfused rabbit hearts with chronic ventricular pacing induced heart failure and in 5 normal hearts at baseline and after ondansetron (100 nM) infusion. APD measured to 80% repolarization (APD80) was determined at a 300 ms pacing cycle length (PCL), and then a dynamic pacing protocol was used to test arrhythmia inducibility. To demonstrate that ondansetron is a specific SK current blocker, ondansetron was either given before (n=3) or after (n=3) apamin in normal rabbit hearts that were Langendorff perfused with a hypokalemic (2.4 mM) Tyrode solution. Ventricular pacing at a 300 ms PCL was performed to determine APD80.
Results: Ondansetron did not change APD80 in normal ventricles. In failing ventricles, the APD80 prolonged from 150±7 ms to 168±5 ms (N=7, P<0.001) by ondansetron. The VF inducibility was 21/45 (47%) at baseline and 21/27 (78%) after adding ondansetron (P=0.013). In 3 hypokalemic normal ventricles, ondansetron prolonged the APD80 from 148±2 ms to 166±3 ms (P=0.025). Subsequent administration of apamin failed to further prolong APD80 (166±3 vs 168±2 ms, P=0.13). In an additional 3 hypokalemic ventricles, apamin prolonged the APD80 from 161±5 ms to 177±5 ms (P=0.009). Subsequent administration of ondansetron failed to further prolong APD80 (177±5 vs 179±6 ms, P=0.118).
Conclusions: IKAS is upregulated in failing ventricles, and ondansetron can block IKAS and cause APD prolongation. This decreases the repolarization reserve, which promotes the increased vulnerability to VF.
Author Disclosures: D. Yin: None. N. Yang: None. Z. Tian: None. A.Z. Wu: None. D. Xu: None. M. Chen: None. Z. Wang: None. Y. Chan: None. Z. Chen: None. S. Lin: None. P. Chen: None. T.H. Everett: None.
- © 2016 by American Heart Association, Inc.